JP2006008621A - Remedy for skin disease - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a remedy for inflammatory keratoses (e.g. psoriasis, parapsoriasis, and lichen), keratoses (e.g. ichthyosis and Darier's disease), or inflammatory skin diseases (e.g. atopic dermatitis and contact dermatitis). <P>SOLUTION: The remedy for inflammatory keratoses, keratoses, or inflammatory skin diseases in human or animal contains as an active ingredient a compound represented by formula (I) or a medicinally acceptable salt thereof. In formula (I), R<SP>1</SP>is a halogen-substituted benzofuranyl or a halogen-substituted styryl; R<SP>2</SP>is a substituted hydroxy, a substituted mercapto, or a substituted sulfonyl; and X is any one of the groups represented by formula (II). <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a therapeutic agent for skin diseases, and more particularly to a therapeutic agent for inflammatory keratosis, keratosis or inflammatory skin diseases.

  Psoriasis, which is a typical disease of inflammatory keratosis, is an intractable skin disease that poses repetitive hatred after its onset, although it has little risk to life. Typical skin rashes in psoriasis are erythema to erythema with thick scales, and are distributed throughout the body, but especially the elbows, knees, vulva (sites subject to external irritation), head and trunk (sites with low light exposure). ). Typical histology includes thickening of the epidermis due to abnormal proliferation of basal keratinocytes (keratinocytes), infiltration of inflammatory cells (lymphocytes and multinucleated leukocytes) into the dermis and epidermis, and edematous with vasodilation of the dermal papillary layer Change is a feature. Thus, psoriasis is a disease characterized mainly by abnormal growth of keratinocytes and skin inflammation.

  To date, steroid external preparations and vitamin D3 derivative external preparations have been the first choice for the treatment of inflammatory keratosis, particularly psoriasis. In cases of resistance to these drugs, phototherapy such as PUVA / UVB therapy, etretinate is taken, and in severe cases, cyclosporine and methotrexate are also taken, but there are still satisfactory treatment effects for each treatment method. The current situation has not been obtained, and the development of an effective and safe treatment for inflammatory keratosis is awaited.

  The cause of psoriasis has not yet been clearly clarified, but numerous inflammatory cells (such as neutrophils, monocytes, and T cells) and lesions infiltrating the epidermis and dermis layer found in pathological images of psoriasis patients Inflammatory mediators such as cytokines such as IL-1, TNF, IL-6, and IL-8, and eicosanoids of arachidonic acid metabolites play an important role in psoriasis inflammatory response and epidermal thickening It is inferred.

  Therefore, it is considered that a drug having an action of suppressing inflammatory reaction and epidermis thickening associated with psoriasis can be one of effective therapeutic agents for inflammatory keratosis, particularly psoriasis.

  On the other hand, the formula (I)

[Wherein R ¹ represents benzofuranyl substituted with halogen, or styryl substituted with halogen;
R ² represents substituted hydroxy, substituted mercapto, or substituted sulfonyl;
X is

Or a pharmaceutically acceptable salt thereof has an inhibitory effect on nitric oxide (NO) production, and includes adult respiratory distress syndrome (ARDS), asthma, cardiovascular ischemia, myocarditis, heart failure It is reported to be useful for the treatment of nitric oxide (NO) mediated diseases in humans or animals such as hypotension, atherosclerosis (see Patent Document 1). However, the compound of formula (I) is effective for inflammatory keratosis (psoriasis, psoriasis, lichen, etc.) and inflammatory skin diseases (atopic dermatitis, contact dermatitis, etc.). It was not known.
International Publication No. 02/055541 Pamphlet

  It is an object of the present invention to provide a novel therapeutic agent for skin diseases, especially a therapeutic agent for inflammatory keratosis, keratosis or inflammatory skin disease, particularly a therapeutic agent for psoriasis and a therapeutic agent for atopic dermatitis. is there.

The inventors of the present invention have found that the compound of the above formula (I) having an NO production inhibitory action is associated with an inflammatory reaction and a variety of animal models (TPA-induced dermatitis, A23187-induced dermatitis) pathologically similar to psoriasis. It was confirmed that it suppresses thickening of the epidermis and was effective as a therapeutic agent for inflammatory keratosis such as psoriasis, psoriasis, and lichen.
The present inventors have also confirmed that the compound of the above formula (I) having an NO production inhibitory action suppresses dermatitis and itching in an atopic dermatitis animal model (DNFB-induced dermatitis model). It has been found that it is effective as a therapeutic agent for inflammatory skin diseases such as dermatitis and contact dermatitis.
It is an object of the present invention to provide a therapeutic agent for inflammatory skin diseases such as inflammatory keratosis such as psoriasis, psoriasis, and lichen, atopic dermatitis, and contact dermatitis.
A further object of the present invention is to provide a therapeutic agent for keratosis (such as ichthyosis and Darier's disease) based on the findings found this time.

The present invention relates to the therapeutic agents shown in the following (1) to (5).
(1) Formula (I)

[Wherein R ¹ represents benzofuranyl substituted with halogen, or styryl substituted with halogen;
R ² represents substituted hydroxy, substituted mercapto, or substituted sulfonyl;
X is

Or a pharmaceutically acceptable salt thereof (hereinafter referred to as compound (I)) as an active ingredient, inflammatory keratosis, keratosis or inflammatory skin disease in humans or animals Therapeutic agent.
(2) The therapeutic agent according to (1), which is a therapeutic agent for inflammatory keratosis in humans or animals.
(3) The therapeutic agent according to (1), which is a therapeutic agent for psoriasis in humans or animals.
(4) The therapeutic agent according to (1), which is a therapeutic agent for inflammatory skin diseases in humans or animals.
(5) The therapeutic agent according to (1), which is a therapeutic agent for atopic dermatitis in humans or animals.

  The pharmaceutical preparation of the present invention containing Compound (I) as an active ingredient is used for inflammatory keratosis (psoriasis, psoriasis, lichen etc.), keratosis (eg ichthyosis, Darier disease etc.), inflammatory skin diseases ( Atopic dermatitis, contact dermatitis, etc.).

  Suitable pharmaceutically acceptable salts of the compounds of formula (I) are the conventional non-toxic salts, including, for example, salts with bases or acid addition salts, for example alkali metal salts (for example sodium Salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), salts with inorganic bases, such as ammonium salts; for example, organic amine salts (eg, triethylamine salts, pyridine salts, picoline salts, Salts with organic bases such as ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N, N′-dibenzylethylenediamine salts, etc .; inorganic acid addition salts (eg hydrochlorides, hydrobromides, sulfates) Organic carboxylic acid or sulfonic acid addition salt (eg, formate, acetate, trifluoroacetate, maleate, tartrate) Citrate, fumarate, methanesulfonate, benzenesulfonate, toluene sulfonate); basic or acidic amino acid (e.g., arginine, aspartic acid, and salts with glutamic acid, etc.).

  Compound (I) may contain one or more stereoisomers such as optical isomers and geometric isomers based on asymmetric carbon atoms and double bonds, but such isomers and their All mixtures are within the scope of the present invention.

  Compound (I) may be in the form of a solvate, which is also within the scope of the present invention. Preferred solvates include hydrates, ethanolates and the like.

  Preferred examples and specific examples of various definitions included in the scope of the present invention used in the description above and hereinafter will be described in detail below.

  “Lower” means a group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise specified.

  Suitable “halogen” includes, for example, fluorine, bromine, chlorine and iodine.

  “Styryl substituted with halogen” means styryl having a halogen atom as a substituent on the benzene ring. Suitable examples of “halogen-substituted styryl” include 2- (2-chlorophenyl) ethenyl, 2- (3-chlorophenyl) ethenyl, 2- (4-chlorophenyl) ethenyl, 2- (2-bromophenyl) Ethenyl, 2- (3-bromophenyl) ethenyl, 2- (4-bromophenyl) ethenyl, 2- (2-fluorophenyl) ethenyl, 2- (3-fluorophenyl) ethenyl, 2- (4-fluorophenyl) And ethenyl.

“Substituted hydroxy” means a group represented by the formula —Y—R ³ (wherein Y represents —O— and R ³ represents a suitable organic group).

“Substituted mercapto” means a group represented by the formula —Y—R ³ (wherein Y represents —S— and R ³ represents a suitable organic group).

“Substituted sulfonyl” means a group represented by the formula —Y—R ³ (wherein Y represents —SO ₂ — and R ³ represents a suitable organic group).

  Examples of the “suitable organic group” include lower alkyl, halo (lower) alkyl, an optionally substituted heterocyclic group and an optionally substituted aryl. Each of the heterocyclic group and aryl may be substituted with one or more, preferably 1 to 3 substituents (for example, lower alkyl, lower alkoxy, halogen, halo (lower) alkyl, etc.).

In the formula —Y—R ³ , Y is preferably —O—.

  Examples of the “heterocyclic group” include a saturated or unsaturated heterocyclic monocyclic group or a condensed heterocyclic group containing a hetero atom selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom.

As preferable examples of the “heterocyclic group”,
Unsaturated 3 to 8 membered (more preferably 5 or 6 membered) heteromonocyclic groups containing 1 to 4 nitrogen atoms such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Triazolyl (eg, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl), tetrazolyl (eg, 1H-tetrazolyl, 2H-tetrazolyl) and the like;
Saturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic groups containing 1-4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl and the like;
Unsaturated fused heterocyclic groups containing from 1 to 4 nitrogen atoms, such as indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl and the like;
Unsaturated 3 to 8 membered (more preferably 5 or 6 membered) heteromonocyclic groups containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl (eg, 1, 2 , 4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl) and the like;
A saturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, such as morpholinyl, sydnonyl, etc .;
An unsaturated condensed heterocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzoxazolyl, benzooxadiazolyl and the like;
Unsaturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic groups containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, isothiazolyl, thiadiazolyl (eg, 1,2 , 3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl), dihydrothiazinyl and the like;
Saturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic groups containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolidinyl;
Unsaturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic groups containing 1 or 2 sulfur atoms, such as thienyl, dihydrodithiinyl and the like;
Unsaturated fused heterocyclic groups containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl, benzothiadiazolyl, imidazolothiadiazolyl and the like;
Unsaturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic groups containing oxygen atoms, such as furyl, etc .;
Saturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic groups containing oxygen atoms, such as tetrahydrofuranyl, tetrahydropyranyl and the like;
A saturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic group containing an oxygen atom and 1 or 2 sulfur atoms, such as dihydrooxathinyl;
Unsaturated fused heterocyclic groups containing 1 or 2 sulfur atoms, such as benzothienyl, benzodithiinyl and the like;
An unsaturated condensed heterocyclic group containing an oxygen atom and one or two sulfur atoms, such as benzooxathinyl, and the like.

  Preferred examples of the heterocyclic group include an unsaturated 5 or 6-membered heterocyclic monocyclic group containing 1 to 4 nitrogen atoms; and an unsaturated 5 containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms. Or a 6-membered heteromonocyclic group is mentioned.

  More preferred examples of the heterocyclic group include pyridyl, pyrazinyl, thiazolyl, pyridazinyl and pyrimidinyl, and particularly preferred examples of the heterocyclic group include pyridyl, pyrazinyl and thiazolyl.

Suitable “aryl” includes C ₆ -C ₁₂ aryl such as phenyl and naphthyl, of which more preferred is phenyl.

Preferred “lower alkyl” and “halo (lower) alkyl” “lower alkyl” moieties include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl and hexyl. include straight-chain or branched alkyl having 1 to 6 carbon atoms such as, those more preferred among them is a C ₁ -C ₄ alkyl.

Suitable “lower alkoxy” includes 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, tert-pentyloxy and hexyloxy. Straight chain or branched alkoxy having a C ₁ -C ₄ alkoxy is more preferable.

  Suitable “halo (lower) alkyl” includes one or more such as trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl and 3,3,3-trifluoropropyl, and more Preferred examples include lower alkyl substituted with 1 to 3 halogen atoms, and more preferred is trihalo (lower) alkyl.

  Preferable examples of the heterocyclic group which may be substituted include 2-pyridyl, 3-pyridyl, 4-pyridyl, 6-methoxy-2-pyridyl, 6-methyl-2-pyridyl, 5-chloro-2- Pyridyl, 6-chloro-2-pyridyl, 3-chloro-2-pyridyl, 3,5-dichloro-2-pyridyl, 3- (trifluoromethyl) -2-pyridyl, 5- (trifluoromethyl) -2- Pyridyl, 2-pyrazinyl, 5-chloro-2-pyrazinyl, 6-chloro-2-pyrazinyl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5 Yl, 5-methyl-1,3-thiazol-2-yl, 5-chloro-1,3-thiazol-2-yl, 3-pyridazinyl, 4-pyridazinyl, 6-chloro-3-pyridazinyl, 6-methoxy- 3 Pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-chloro-4-pyrimidinyl, 6- (trifluoromethyl) -4-pyrimidinyl, such as 2- (trifluoromethyl) -4-pyrimidinyl and the like.

  Preferable examples of the optionally substituted aryl include phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl and 2- (trifluoromethyl). Examples include phenyl, 3- (trifluoromethyl) phenyl, 4- (trifluoromethyl) phenyl, and the like.

  In formula (I), the formula:

The group represented by

And more preferably

And particularly preferably

It is.

The following are mentioned as a suitable aspect of compound (I).
(1) R ² is a formula: —Y—R ³ (wherein R ³ is lower alkyl, halo (lower) alkyl, an optionally substituted heterocyclic group, or an optionally substituted aryl; Y is -O -, - S- or -SO ₂ - is a group represented by a is) acceptable salt thereof compound or pharmaceutical of formula (I).

(2) R ³ is lower alkyl; halo (lower) alkyl; heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and halo (lower) alkyl Or a pharmaceutically acceptable compound according to (1), which is an aryl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and halo (lower) alkyl Its salt.

(3) R ³ is lower alkyl; halo (lower) alkyl; a heterocyclic group selected from the group consisting of pyridyl, pyrazinyl, thiazolyl, pyridazinyl and pyrimidinyl, wherein the heterocyclic group is lower alkyl, lower alkoxy, halogen and Optionally substituted with one or more substituents selected from the group consisting of halo (lower) alkyl; or one or more selected from the group consisting of lower alkyl, lower alkoxy, halogen and halo (lower) alkyl The compound according to (2) or a pharmaceutically acceptable salt thereof, which is phenyl optionally substituted by a substituent of:

(4) X is

A compound of formula (I) or a pharmaceutically acceptable salt thereof.

(5) The compound according to (4) or a pharmaceutically acceptable salt thereof, wherein R ² is substituted hydroxy.

(6) R ² is represented by the formula: —O—R ³ (wherein R ³ is lower alkyl, halo (lower) alkyl, optionally substituted heterocyclic group, or optionally substituted aryl). (5) or a pharmaceutically acceptable salt thereof.

(7) R ³ is lower alkyl, halo (lower) alkyl, pyridyl, pyrazinyl, thiazolyl or phenyl, and the pyridyl, pyrazinyl, thiazolyl and phenyl are lower alkyl, lower alkoxy, halogen and halo (lower) alkyl, respectively. The compound according to (6) or a pharmaceutically acceptable salt thereof, which may be substituted with one or more substituents selected from the group consisting of:

(8) R ³ is lower alkyl, halo (lower) alkyl, pyridyl, pyrazinyl, thiazolyl or phenyl, and the pyridyl is one or more selected from the group consisting of lower alkyl, lower alkoxy, halogen and halo (lower) alkyl The compound according to (7) or a pharmaceutically acceptable salt thereof, which may be substituted with the above substituents.

(9) A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ¹ is benzofuranyl substituted with chlorine, or styryl substituted with chlorine.

(10) A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ¹ is 5-chloro-1-benzofuran-2-yl or 2- (4-chlorophenyl) ethenyl.

The following compounds are mentioned as an example of compound (I).
(1) (2E) -3- (4-Chlorophenyl) -N-[(1S) -2-oxo-2-([2-oxo-2- [4- (1,3-thiazol-2-yloxy)] -1-piperidinyl] ethyl] amino) -1- (2-pyridylmethyl) ethyl] acrylamide (2) 5-chloro-N-[(1S) -2-oxo-2-([2-oxo-2- [ 4- (1,3-thiazol-2-yloxy) -1-piperidinyl] ethyl] amino) -1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (3) (2E) -3- (4-Chlorophenyl) -N-[(1S) -2-oxo-2-([2-oxo-2- [4- (2-pyrazinyloxy) -1-piperidinyl] ethyl] amino) -1- (2- Pyridylmethyl) ethyl] acrylamide ( ) 5-Chloro-N-[(1S) -2-oxo-2-([2-oxo-2- [4- (2-pyrazinyloxy) -1-piperidinyl] ethyl] amino) -1- (2-pyridyl) Methyl) ethyl] -1-benzofuran-2-carboxamide (5) (2E) -3- (4-chlorophenyl) -N-[(1S) -2-oxo-2-([2-oxo-2- [4 -(4-Pyridyloxy) -1-piperidinyl] ethyl] amino) -1- (2-pyridylmethyl) ethyl] acrylamide (6) 5-chloro-N-[(1S) -2-oxo-2-([ 2-Oxo-2- [4- (4-pyridyloxy) -1-piperidinyl] ethyl] amino) -1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (7) (2E)- 3- (4-Chloropheny ) -N-[(1S) -2-oxo-2-([2-oxo-2- [4- (3-pyridyloxy) -1-piperidinyl] ethyl] amino) -1- (2-pyridylmethyl) Ethyl] acrylamide (8) 5-chloro-N-[(1S) -2-oxo-2-([2-oxo-2- [4- (3-pyridyloxy) -1-piperidinyl] ethyl] amino)- 1- (2-Pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (9) (2E) -3- (4-Chlorophenyl) -N-[(1S) -2-[(2- [4- [ (6-Methoxy-2-pyridyl) oxy] -1-piperidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] acrylamide (10) 5-chloro-N-[( 1S) -2-[(2- [4- [ 6-methoxy-2-pyridyl) oxy] -1-piperidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide

(11) (2E) -3- (4-Chlorophenyl) -N-[(1S) -2-[(2- [3-[(5-chloro-2-pyridyl) oxy] -1-piperidinyl] -2 -Oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] acrylamide (12) 5-chloro-N-[(1S) -2-[(2- [3-[(5-chloro- 2-Pyridyl) oxy] -1-piperidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (13) (2E) -3- (4-Chlorophenyl) -N-[(1S) -2-oxo-2-([2-oxo-2- [4- (2-pyridyloxy) -1-piperidinyl] ethyl] amino) -1- (2 -Pyridylmethyl) ethyl] acrylami (14) 5-chloro-N-[(1S) -2-oxo-2-([2-oxo-2- [4- (2-pyridyloxy) -1-piperidinyl] ethyl] amino) -1- ( 2-Pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (15) (2E) -3- (4-Chlorophenyl) -N-[(1S) -2-[(2- [4-[(6- Methyl-2-pyridyl) oxy] -1-piperidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] acrylamide (16) 5-chloro-N-[(1S)- 2-[(2- [4-[(6-Methyl-2-pyridyl) oxy] -1-piperidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -1 -Benzofuran-2-carboxami (17) (2E) -3- (4-Chlorophenyl) -N-[(1S) -2-[(2- [4-[(6-chloro-2-pyridyl) oxy] -1-piperidinyl] -2 -Oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] acrylamide (18) 5-chloro-N-[(1S) -2-[(2- [4-[(6-chloro- 2-Pyridyl) oxy] -1-piperidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (19) (2E) -3- (4-Chlorophenyl) -N-[(1S) -2-oxo-2-[[2-oxo-2- (4-[[5- (trifluoromethyl) -2-pyridyl] oxy] -1-piperidinyl ) Ethyl] amino] -1- (2-pyri) Dilmethyl) ethyl] acrylamide (20) 5-chloro-N-[(1S) -2-oxo-2-[[2-oxo-2- (4-[[5- (trifluoromethyl) -2-pyridyl] Oxy] -1-piperidinyl) ethyl] amino] -1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide

(21) (2E) -3- (4-Chlorophenyl) -N-[(1S) -2-[(2- [4-[(5-chloro-2-pyridyl) oxy] -1-piperidinyl] -2 -Oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] acrylamide (22) 5-chloro-N-[(1S) -2-[(2- [4-[(5-chloro- 2-Pyridyl) oxy] -1-piperidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (23) (2E) -3- (4-Chlorophenyl) -N-[(1S) -2-oxo-2-[[2-oxo-2- (4-phenoxy-1-piperidinyl) ethyl] amino] -1- (2-pyridylmethyl) ethyl Acrylamide (24) 5 -Chloro-N-[(1S) -2-oxo-2-[[2-oxo-2- (4-phenoxy-1-piperidinyl) ethyl] amino] -1- (2-pyridylmethyl) ethyl] -1 -Benzofuran-2-carboxamide (25) (2E) -3- (4-Chlorophenyl) -N-[(1S) -2-oxo-2-([2-oxo-2- [4- (2,2, 2-trifluoroethoxy) -1-piperidinyl] ethyl] amino) -1- (2-pyridylmethyl) ethyl] acrylamide (26) 5-chloro-N-[(1S) -2-oxo-2-([2 -Oxo-2- [4- (2,2,2-trifluoroethoxy) -1-piperidinyl] ethyl] amino) -1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (27) (2E) -3- (4 Chlorophenyl) -N-[(1S) -2-[[2- (4-Isopropoxy-1-piperidinyl) -2-oxoethyl] amino] -2-oxo-1- (2-pyridylmethyl) ethyl] acrylamide ( 28) 5-Chloro-N-[(1S) -2-[[2- (4-isopropoxy-1-piperidinyl) -2-oxoethyl] amino] -2-oxo-1- (2-pyridylmethyl) ethyl ] -1-benzofuran-2-carboxamide (29) (2E) -N-[(1S) -2-[[2- (4-butoxy-1-piperidinyl) -2-oxoethyl] amino] -2-oxo- 1- (2-Pyridylmethyl) ethyl] -3- (4-chlorophenyl) acrylamide (30) N-[(1S) -2-[[2- (4-butoxy-1-piperidinyl) -2-oxoethyl ] Amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -5-chloro-1-benzofuran-2-carboxamide

(31) (2E) -3- (4-Chlorophenyl) -N-[(1S) -2-[(2- [4-[(6-chloro-2-pyrazinyl) oxy] -1-piperidinyl] -2 -Oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -2-propenamide (32) 5-chloro-N-[(1S) -2-[(2- [4-[( 6-chloro-2-pyrazinyl) oxy] -1-piperidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (33) (2E ) -3- (4-Chlorophenyl) -N-[(1S) -2-[(2- [4-[(6-chloro-3-pyridazinyl) oxy] -1-piperidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridy Methyl) ethyl] -2-propenamide (34) 5-chloro-N-[(1S) -2-[(2- [4-[(6-chloro-3-pyridazinyl) oxy] -1-piperidinyl]- 2-Oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (35) (2E) -3- (4-chlorophenyl) -N-[(1S) -2-[(2- [4-[(6-methoxy-3-pyridazinyl) oxy] -1-piperidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl]- 2-propenamide (36) 5-chloro-N-[(1S) -2-[(2- [4-[(6-methoxy-3-pyridazinyl) oxy] -1-piperidinyl] -2-oxoethyl) amino ] -2-Oki -1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (37) (2E) -3- (4-chlorophenyl) -N-[(1S) -2-[(2- [4- [(3-Chloro-2-pyridyl) oxy] -1-piperidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -2-propenamide (38) 5-chloro -N-[(1S) -2-[(2- [4-[(3-chloro-2-pyridyl) oxy] -1-piperidinyl] -2-oxoethyl) amino] -2-oxo-1- (2 -Pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (39) (2E) -3- (4-chlorophenyl) -N-[(1S) -2-[(2- [4-[(6-chloro -4-pyrimidinyl) oxy] -1-pi Peridinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -2-propenamide (40) 5-chloro-N-[(1S) -2-[(2- [ 4-[(6-Chloro-4-pyrimidinyl) oxy] -1-piperidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide

(41) (2E) -3- (4-Chlorophenyl) -N-[(1S) -2-oxo-2-[[2-oxo-2- (4-[[6- (trifluoromethyl) -4 -Pyrimidinyl] oxy] -1-piperidinyl) ethyl] amino] -1- (2-pyridylmethyl) ethyl] -2-propenamide (42) 5-chloro-N-[(1S) -2-oxo-2- [[2-oxo-2- (4-[[6- (trifluoromethyl) -4-pyrimidinyl] oxy] -1-piperidinyl) ethyl] amino] -1- (2-pyridylmethyl) ethyl] -1- Benzofuran-2-carboxamide (43) 5-chloro-N-[(1S) -2-oxo-2-[[2-oxo-2- (4-[[2- (trifluoromethyl) -4-pyrimidinyl] Oxy] -1-piperidinyl) ethyl] Mino] -1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (44) 5-chloro-N-[(1S) -2-[(2- [4-[(5-chloro- 2-pyrazinyl) oxy] -1-piperidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (45) (2E) -3- (4-Chlorophenyl) -N-[(1S) -2-[(2- [4-[(5-methyl-1,3-thiazol-2-yl) oxy] -1-piperidinyl] -2-oxoethyl) Amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -2-propenamide (46) 5-chloro-N-[(1S) -2-[(2- [4-[(5-methyl) -1,3-thiazol-2-yl) oki ] -1-Piperidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (47) (2E) -3- (4-chlorophenyl) -N-[(1S) -2-[(2- [4-[(5-chloro-1,3-thiazol-2-yl) oxy] -1-piperidinyl] -2-oxoethyl) amino] -2- Oxo-1- (2-pyridylmethyl) ethyl] -2-propenamide (48) 5-chloro-N-[(1S) -2-[(2- [4-[(5-chloro-1,3- Thiazol-2-yl) oxy] -1-piperidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (49) (2E)- 3- (4-Chloroph Enyl) -N-[(1S) -2-[(2-[(3R) -3-[(5-chloro-2-pyridyl) oxy] -1-pyrrolidinyl] -2-oxoethyl) amino] -2- Oxo-1- (2-pyridylmethyl) ethyl] -2-propenamide (50) 5-chloro-N-[(1S) -2-[(2-[(3R) -3-[(5-chloro- 2-pyridyl) oxy] -1-pyrrolidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide

(51) (2E) -3- (4-Chlorophenyl) -N-[(1S) -2-[(2-[(3S) -3-[(5-chloro-2-pyridyl) oxy] -1- Pyrrolidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -2-propenamide (52) 5-chloro-N-[(1S) -2-[(2- [ (3S) -3-[(5-Chloro-2-pyridyl) oxy] -1-pyrrolidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -1-benzofuran- 2-carboxamide (53) (2E) -3- (4-chlorophenyl) -N-[(1S) -2-[(2-[(3R) -3-[(6-chloro-2-pyrazinyl) oxy] -1-pyrrolidinyl] -2-oxoethyl) amino] -2- Xo-1- (2-pyridylmethyl) ethyl] -2-propenamide (54) 5-chloro-N-[(1S) -2-[(2-[(3R) -3-[(6-chloro- 2-Pyrazinyl) oxy] -1-pyrrolidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (55) (2E) -3- (4-Chlorophenyl) -N-[(1S) -2-[(2-[(3R) -3-[(5-methyl-1,3-thiazol-2-yl) oxy] -1-pyrrolidinyl]- 2-Oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -2-propenamide (56) 5-chloro-N-[(1S) -2-[(2-[(3R) -3-[(5-Methyl-1,3-thiazole-2- L) oxy] -1-pyrrolidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (57) (2E) -3- (4 -Chlorophenyl) -N-[(1S) -2-oxo-2-[[2-oxo-2- (3-[[6- (trifluoromethyl) -4-pyrimidinyl] oxy] -1-azetidinyl) ethyl Amino] -1- (2-pyridylmethyl) ethyl] -2-propenamide (58) 5-chloro-N-[(1S) -2-oxo-2-[[2-oxo-2- (4- [[6- (Trifluoromethyl) -4-pyrimidinyl] oxy] -1-azetidinyl) ethyl] amino] -1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (59) (2E) − 3- (4-Chlorophenyl) -N-[(1S) -2-[(2- [4-[(3,5-dichloro-2-pyridyl) oxy] -1-piperidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -2-propenamide (60) 5-chloro-N-[(1S) -2-[(2- [4-[(3,5-dichloro) -2-pyridyl) oxy] -1-piperidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide

(61) (2E) -3- (4-Chlorophenyl) -N-[(1S) -2-oxo-2-[[2-oxo-2- (4-[[3- (trifluoromethyl) -2 -Pyridyl] oxy] -1-piperidinyl) ethyl] amino] -1- (2-pyridylmethyl) ethyl] -2-propenamide (62) 5-chloro-N-[(1S) -2-oxo-2- [[2-oxo-2- (4-[[3- (trifluoromethyl) -2-pyridyl] oxy] -1-piperidinyl) ethyl] amino] -1- (2-pyridylmethyl) ethyl] -1- Benzofuran-2-carboxamide (63) (2E) -3- (4-Chlorophenyl) -N-[(1S) -2-([2- [4- (4-fluorophenoxy) -1-piperidinyl] -2- Oxoethyl] amino) -2-oxo-1- 2-Pyridylmethyl) ethyl] -2-propenamide (64) 5-chloro-N-[(1S) -2-([2- [4- (4-fluorophenoxy) -1-piperidinyl] -2-oxoethyl Amino) -2-oxo-1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (65) (2E) -3- (4-chlorophenyl) -N-[(1S) -2- Oxo-2-[(2-oxo-2- [4- [4- (trifluoromethyl) phenoxy] -1-piperidinyl] ethyl) amino] -1- (2-pyridylmethyl) ethyl] -2-propenamide (66) 5-chloro-N-[(1S) -2-oxo-2-[(2-oxo-2- [4- [4- (trifluoromethyl) phenoxy] -1-piperidinyl] ethyl) amino] -1- (2 Pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (67) (2E) -3- (4-chlorophenyl) -N-[(1S) -2-([2- [4- (4-chlorophenoxy)] -1-piperidinyl] -2-oxoethyl] amino) -2-oxo-1- (2-pyridylmethyl) ethyl] -2-propenamide (68) 5-chloro-N-[(1S) -2-([ 2- [4- (4-Chlorophenoxy) -1-piperidinyl] -2-oxoethyl] amino) -2-oxo-1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (69) ( 2E) -3- (4-Chlorophenyl) -N-[(1S) -2-oxo-2-([2-oxo-2- [4- (2-pyridylthio) -1-piperidinyl] ethyl] amino)- 1- (2 -Pyridylmethyl) ethyl] -2-propenamide (70) 5-chloro-N-[(1S) -2-oxo-2-([2-oxo-2- [4- (2-pyridylthio) -1- Piperidinyl] ethyl] amino) -1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide

(71) (2E) -3- (4-Chlorophenyl) -N-[(1S) -2-oxo-2-([2-oxo-2- [4- (2-pyridylsulfonyl) -1-piperidinyl] Ethyl] amino) -1- (2-pyridylmethyl) ethyl] -2-propenamide (72) 5-chloro-N-[(1S) -2-oxo-2-([2-oxo-2- [4 -(2-pyridylsulfonyl) -1-piperidinyl] ethyl] amino) -1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (73) (2E) -3- (4-chlorophenyl)- N-[(1S) -2-[(2- [4-[(5-chloro-2-pyridyl) thio] -1-piperidinyl] -2-oxoethyl) amino] -2-oxo-1- (2- Pyridylmethyl) ethyl] -2-propene (74) 5-chloro-N-[(1S) -2-[(2- [4-[(5-chloro-2-pyridyl) thio] -1-piperidinyl] -2-oxoethyl) amino] -2 -Oxo-1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (75) (2E) -3- (4-chlorophenyl) -N-[(1S) -2-oxo-2- ( [2-Oxo-2- [4- (4-pyridylthio) -1-piperidinyl] ethyl] amino) -1- (2-pyridylmethyl) ethyl] -2-propenamide (76) 5-chloro-N- [ (1S) -2-oxo-2-([2-oxo-2- [4- (4-pyridylthio) -1-piperidinyl] ethyl] amino) -1- (2-pyridylmethyl) ethyl] -1-benzofuran -2-Carboxamide (77) (2 ) -3- (4-Chlorophenyl) -N-[(1S) -2-[(2- [4-[(4-chlorophenyl) thio] -1-piperidinyl] -2-oxoethyl) amino] -2-oxo -1- (2-pyridylmethyl) ethyl] -2-propenamide (78) 5-chloro-N-[(1S) -2-[(2- [4-[(4-chlorophenyl) thio] -1- Piperidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide (79) (2E) -3- (4-chlorophenyl) -N- [ (1S) -2-[(2- [4-[(4-Chlorophenyl) sulfonyl] -1-piperidinyl] -2-oxoethyl) amino] -2-oxo-1- (2-pyridylmethyl) ethyl] -2 -Propenamide ( 80) 5-Chloro-N-[(1S) -2-[(2- [4-[(4-chlorophenyl) sulfonyl] -1-piperidinyl] -2-oxoethyl) amino] -2-oxo-1- ( 2-Pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide

Compound (I) and the specific compounds described above are known compounds, and can be prepared by the methods described in the following publications or by methods similar thereto (with reference to this publication, which is hereby incorporated by reference) And).
International Publication No. 02/055541 Pamphlet

  The therapeutic agent for skin diseases of the present invention contains a pharmaceutical preparation, for example, compound (I) as an active ingredient, and is rectal, pulmonary (nasal or oral cavity inhalation), nasal, intraocular, external (topical). ), Solid, semi-solid or liquid suitable for oral or parenteral (including subcutaneous, intravenous and intramuscular) administration or insufflation (eg tablets, pellets, troches, capsules, suppositories, creams, ointments) Agents, aerosols, powders, solutions, emulsions, suspensions, etc.). Of these, external (topical) administration is preferred, and creams and ointments are preferred.

  The pharmaceutical composition of the present invention comprises various organic or inorganic carriers conventionally used for pharmaceutical purposes, such as excipients (for example, sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc.) , Binders (eg cellulose, methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, starch etc.), disintegrants (eg starch, carboxymethylcellulose, carboxymethylcellulose calcium, hydroxypropyl starch, starch glycolic acid) Sodium, sodium bicarbonate, calcium phosphate, calcium citrate, etc.), lubricants (eg magnesium stearate, talc, lauric) Sodium sulfate, etc.), flavoring agents (eg, citric acid, menthol, glycine, orange peel), preservatives (eg, sodium benzoate, sodium bisulfite, methyl paraben, propyl paraben), stabilizers (eg, citric acid, citric acid) Contains sodium, acetic acid, etc., suspending agents (eg methylcellulose, polyvinylpyrrolidone, aluminum stearate), dispersants, aqueous diluents (eg water), base waxes (eg cocoa butter, polyethylene glycol, white petrolatum, etc.) can do.

  Compound (I) may be usually administered 1 to 4 times a day at a unit dose of 0.01 mg / kg to 500 mg / kg. However, the above dose can be increased or decreased depending on the age, weight, condition or method of administration of the patient.

  When administering Compound (I) as a lotion, gel, cream or ointment, a concentration of 0.001 to 50% by weight (preferably 0.01 to 10% by weight) of Compound (I) is administered several times daily, for example daily. Can be administered topically 1 to 5 times.

The pharmacological test results of typical examples of compound (I) are shown below.
[1] Test compound Compound (a): (2E) -3- (4-Chlorophenyl) -N-[(1S) -2-oxo-2-[[2-oxo-2- (4-[[6- (Trifluoromethyl) -4-pyrimidinyl] oxy] -1-piperidinyl) ethyl] amino] -1- (2-pyridylmethyl) ethyl] -2-propenamide compound (b): 5-chloro-N-[( 1S) -2-oxo-2-[[2-oxo-2- (4-[[6- (trifluoromethyl) -4-pyrimidinyl] oxy] -1-piperidinyl) ethyl] amino] -1- (2 -Pyridylmethyl) ethyl] -1-benzofuran-2-carboxamide

[2] Test method for effects on experimental animal model of inflammation in psoriasis (TPA-induced mouse dermatitis model) TPA (12-O-tetradecanoylphore) was placed on the auricle of a BDF1 female mouse (7 weeks old) on the 0th day. Ball-13-acetate) was applied at 2 μg / ear to induce dermatitis. Test drug is dissolved in solvent (ethanol) at concentrations of 0.3%, 1.0%, 3.0% (w / v%), and every day (Day 0 is 15 minutes before TPA application) 40 μl was applied to the part. After 6 hours of TPA application, the thickness of the auricle was measured with a Peacock dial thick gage, and the swelling of the auricle was used as an index of the inflammatory reaction. 100% suppression of normal auricle thickness, 0% suppression of auricle part (vehicle group) coated with TPA and solvent instead of test drug, to suppress auricular swelling of test drug The rate (%) was calculated. The test animals were sacrificed on the 4th day, the auricles were cut, fixed with 10% formalin buffer, embedded in paraffin, and sliced to prepare hematoxylin-eosin stained specimens. This specimen was photographed under a microscope, and the thickness of the epidermis layer was measured. The epidermis of the test drug is controlled by suppressing the thickness of the epidermis of the normal auricle by 100%, and suppressing the thickness of the epidermis (vehicle group) coated with TPA and solvent instead of the test drug by 0%. The inhibition rate (%) of thickening was calculated.

Test results:
The results are shown in Tables 1 and 2.

[3] Test method for effect on experimental animal model of inflammation in psoriasis (TPA-induced mouse dermatitis model) 2 μg / ear of TPA was applied to the auricle of BDF1 female mice (5 weeks old) on the 0th and 2nd days And induced dermatitis. The test drug was dissolved in a solvent (DMSO: ethanol: acetone = 5: 45: 50) at a concentration of 1.0% and 3.0% (w / v%), and every day (on the 0th and 2nd days) 15 minutes before TPA application) 40 μl was applied to the auricle. The thickness of the auricle was measured with a Peacock dial thick gage 6 hours after the application of TPA on the 0th and 2nd days, and the swelling of the auricle was used as an index of the inflammatory reaction. 100% suppression of normal auricle thickness, 0% suppression of auricle part (vehicle group) coated with TPA and solvent instead of test drug, to suppress auricular swelling of test drug The rate (%) was calculated. The test animals were sacrificed on the 4th day, the auricles were cut, fixed with 10% formalin buffer, embedded in paraffin, and sliced to prepare hematoxylin-eosin stained specimens. This specimen was photographed under a microscope, and the thickness of the epidermis layer was measured. The epidermis of the test drug is controlled by suppressing the thickness of the epidermis of the normal auricle by 100%, and suppressing the thickness of the epidermis (vehicle group) coated with TPA and solvent instead of the test drug by 0%. The inhibition rate (%) of thickening was calculated.

Test results:
The results are shown in Table 3 and Table 4.

[4] Method for testing effect on experimental animal model of inflammation in psoriasis (TPA-induced mouse dermatitis model) On the auricular part of a BDF1 female mouse (7 weeks old), 0th day, 2nd day, 4th day, 7th day On the eyes and 9th day, TPA was applied at 1 μg / ear to induce dermatitis. The test drug was dissolved in a solvent (DMSO: ethanol: acetone = 5: 45: 50) at a concentration of 0.3%, 1.0%, 3.0% (w / v%), and from the 7th day, 10 Each day until the day (the first administration on the 7th and 9th day was 15 minutes before TPA application), 40 μl was applied to the auricle part twice a day (on the 10th day once). On the 10th day, the thickness of the auricle was measured with a Peacock dial thick gage, and the swelling of the auricle was used as an index of the inflammatory reaction. 100% suppression of normal auricle thickness, 0% suppression of auricle part (vehicle group) coated with TPA and solvent instead of test drug, to suppress auricular swelling of test drug The rate (%) was calculated. The test animals were sacrificed on the 10th day, the auricles were cut, fixed with 10% formalin buffer, embedded in paraffin, and sliced to prepare hematoxylin-eosin stained specimens. This specimen was photographed under a microscope, and the thickness of the epidermis layer was measured. The epidermis of the test drug is controlled by suppressing the thickness of the epidermis of the normal auricle by 100%, and suppressing the thickness of the epidermis (vehicle group) coated with TPA and solvent instead of the test drug by 0%. The inhibition rate (%) of thickening was calculated.

Test results:
The results are shown in Tables 5 and 6.

[5] Effect on experimental animal model of inflammation in psoriasis (A23187-induced mouse dermatitis model) In this A23187-induced mouse dermatitis model, edema (auricular swelling) and infiltration of inflammatory cells are observed. These inflammatory reactions are believed to be due to eicosanoids produced by A23187 stimulation, in particular LTB4 (leukotriene B4). It is known that LTB4 not only induces an inflammatory reaction such as edema and neutrophil infiltration but also acts as a keratinocyte growth factor as an inflammatory mediator. Therefore, it is considered that this model is suitable as an experimental animal model for evaluating the inflammatory response in psoriasis, rather than an evaluation system that looks at the anti-inflammatory effect of a simple drug (EJ 139: 11-18, 1987). reference).

Test Method BALB / c female mice (8 weeks old) were applied with 20 μg / ear of calcium ionophore (A23187) dissolved in 10% DMSO-acetone solution on the right auricle to induce dermatitis. The test drug was dissolved in a solvent (DMSO: ethanol: acetone = 5: 45: 50) at concentrations of 0.3%, 1.0%, 3.0% (w / v%), and 15 minutes before induction 40 μl was applied to the right auricle of the mouse. At 6 hours and 24 hours after induction, the thickness of the auricle was measured with a Peacock dial thickness gage, and the swelling of the auricle was used as an index of the inflammatory reaction. 100% suppression of normal auricle thickness, 0% suppression of auricular part (vehicle group) coated with A23187 and solvent instead of test drug, suppression of test drug ear swelling The rate (%) was calculated. In addition, 24 hours after induction, myeloperoxidase (MPO) activity in the auricle was measured and used as an index of neutrophil infiltration. 100% inhibition of MPO activity in the normal group, 0% inhibition of MPO activity in the auricle (vehicle group) where A23187 was applied and solvent was applied instead of the test agent, and the inhibition rate of neutrophil infiltration of the test agent (%) Was calculated.

Test results:
The results are shown in Table 7 and Table 8.

[6] Test method for effects on experimental animal model of inflammation in atopic dermatitis (DNFB-induced mouse dermatitis model) DNP- mixed with alum on day 0 in the abdominal cavity of NC / Nga female mice (9 weeks old) Sensitization was performed by injecting 10 μg of Ascaris. Dissolve DNFB (dinitrofluorobenzene) in a solvent (acetone) at a concentration of 0.15% (v / v%), and apply 20 μl to the right auricle once a week for 3 consecutive weeks from the 7th day. did. The test drug is dissolved in a solvent (acetone) at a concentration of 1.0% and 3.0% (w / v%), and the day before, the day of the day (one hour before the application of DNFB) and the next day 20 μl was applied to the right auricle. One hour before the final application of DNFB (before the final application of the test drug), the degree of right auricular dermatitis was visually observed, and 0 (normal), 1 (erythema / scale), 2 (swelling / wound) ), 3 (hardening / scab), 4 (atrophy / defect), and the score was used as an index of dermatitis. The average score of the auricle part where the solvent was applied instead of DNFB was suppressed by 100%, and the average value of the auricle part (vehicle group) where the solvent was applied instead of the test drug after applying DNFB was 0%. As inhibition, the inhibition rate (%) of the dermatitis score of the test drug was calculated. Thirty minutes after the final application of DNFB, the number of scratches was measured with a stagnation measuring device (coil-sensitive activity meter) for 60 minutes, which was used as an index of itchiness. The average value of the number of scratches of the auricle part where the solvent was applied instead of DNFB was suppressed by 100%, and the average value of the number of times of scratching of the auricle part (vehicle group) where the solvent was applied instead of the test drug after applying DNFB As 0% inhibition, the inhibition rate (%) of the number of scratches of the test drug was calculated. The test animals used 7 to 14 animals per group.

Test results:
The results are shown in Table 9 and Table 10.

  As described above, the compound (I) having an NO production inhibitory effect is effective in increasing the thickness of the epidermis and infiltration of inflammatory cells into inflamed tissues in experimental animal models of inflammation in psoriasis (TPA-induced dermatitis model, A23187-induced dermatitis model). It was found to suppress and have anti-inflammatory action. Furthermore, it has been clarified that Compound (I) has the effect of improving the symptoms of atopic dermatitis and suppressing itching in an atopic dermatitis animal model (DNFB-induced dermatitis model).

  Therefore, a pharmaceutical preparation containing compound (I) as an active ingredient is used to treat inflammatory keratosis (psoriasis, psoriasis, lichen, etc.), inflammatory skin diseases (atopic dermatitis, contact dermatitis, etc.) It has been shown to be effective as a medicine. Furthermore, the findings found this time strongly suggested that a pharmaceutical preparation containing compound (I) as an active ingredient is effective as a therapeutic agent for keratosis (such as ichthyosis and Darier's disease).

Claims (5)

Formula (I)

[Wherein R ¹ represents benzofuranyl substituted with halogen, or styryl substituted with halogen;
R ² represents substituted hydroxy, substituted mercapto, or substituted sulfonyl;
X is

Or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic agent for inflammatory keratosis, keratosis or inflammatory skin disease in humans or animals.   The therapeutic agent according to claim 1, which is a therapeutic agent for inflammatory keratosis in humans or animals.   The therapeutic agent according to claim 1, which is a therapeutic agent for psoriasis in humans or animals.   The therapeutic agent according to claim 1, which is a therapeutic agent for inflammatory skin diseases in humans or animals.   The therapeutic agent according to claim 1, which is a therapeutic agent for atopic dermatitis in humans or animals.